Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase (“MAP3K”) family that activates the c-Jun N-terminal protein kinase (“JNK”) and p38 MAP kinase (Ichijo, H., Nishida, E., Irie, K., Dijke, P. T., Saitoh, M., Moriguchi, T., Matsumoto, K., Miyazono, K., and Gotoh, Y. (1997) Science, 275, 90-94). ASK1 is activated by a variety of stimuli including oxidative stress, reactive oxygen species (ROS), LPS, TNF-α, FasL, ER stress, and increased intracellular calcium concentrations (Hattori, K., Naguro, I., Runchel, C., and Ichijo, H. (2009) Cell Comm. Signal. 7:1-10; Takeda, K., Noguchi, T., Naguro, I., and Ichijo, H. (2007) Annu. Rev. Pharmacol. Toxicol. 48: 1-8.27; Nagai, H., Noguchi. T., Takeda, K., and Ichijo, I. (2007) J. Biochem. Mol. Biol. 40:1-6). Phosphorylation of ASK1 protein can lead to apoptosis or other cellular responses depending on the cell type. ASK1 activation and signaling have been reported to play an important role in a broad range of diseases including neurodegenerative, cardiovascular, inflammatory, autoimmune, and metabolic disorders. In addition, ASK1 has been implicated in mediating organ damage following ischemia and reperfusion of the heart, brain, and kidney (Watanabe et al. (2005) BBRC 333, 562-567; Zhang et al., (2003) Life Sci 74-37-43; Terada et al. (2007) BBRC 364: 1043-49).
ROS are reported be associated with increases of inflammatory cytokine production, fibrosis, apoptosis, and necrosis in the kidney. (Singh D K, Winocour P, Farrington K. Oxidative stress in early diabetic nephropathy: fueling the fire. Nat Rev Endocrinol 2011 March; 7(3):176-184; Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001 Dec. 13; 414(6865):813-820; Mimura I, Nangaku M. The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease. Nat Rev Nephrol 2010 November; 6(11):667-678).
Moreover, oxidative stress facilitates the formation of advanced glycation end-products (AGEs) that cause further renal injury and production of ROS. (Hung K Y, et al. N-acetylcysteine-mediated antioxidation prevents hyperglycemia-induced apoptosis and collagen synthesis in rat mesangial cells. Am J Nephrol 2009; 29(3):192-202).
Tubulointerstitial fibrosis in the kidney is a strong predictor of progression to renal failure in patients with chronic kidney diseases (Schainuck L I, et al. Structural-functional correlations in renal disease. Part II: The correlations. Hum Pathol 1970; 1: 631-641.). Unilateral ureteral obstruction (UUO) in rats is a widely used model of tubulointerstitial fibrosis. UUO causes tubulointerstital inflammation, increased expression of transforming growth factor beta (TGF-β), and accumulation of myofibroblasts, which secrete matrix proteins such as collagen and fibronectin. The UUO model can be used to test for a drug's potential to treat chronic kidney disease by inhibiting renal fibrosis (Chevalier et al., Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy, Kidney International (2009) 75, 1145-1152.
Thus, therapeutic agents that function as inhibitors of ASK1 signaling have the potential to remedy or improve the lives of patients in need of treatment for diseases or conditions such as neurodegenerative, cardiovascular, inflammatory, autoimmune, and metabolic disorders. In particular, ASK1 inhibitors have the potential to treat cardio-renal diseases, including kidney disease, diabetic kidney disease, chronic kidney disease, fibrotic diseases (including lung and kidney fibrosis), respiratory diseases (including chronic obstructive pulmonary disease (COPD) and acute lung injury), acute and chronic liver diseases.
U.S. Publication No. 2007/0276050 describes methods for identifying ASK1 inhibitors useful for preventing and/or treating cardiovascular disease and methods for preventing and/or treating cardiovascular disease in an animal.
WO2009027283 discloses triazolopyridine compounds, methods for preparation thereof and methods for treating autoimmune disorders, inflammatory diseases, cardiovascular diseases and neurodegenerative diseases.
U.S. Patent Publication No. 2001/00095410A1, published Jan. 13, 2011, discloses compounds useful as ASK-1 inhibitors. U.S. Patent Publication 2001/00095410A1 relates to compounds of Formula (I):
wherein:                R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, all of which are optionally substituted with 1, 2, or 3 substituents selected from halo, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, —NO2, R6, —C(O)—R6, —OC(O)—R6 —C(O)—O—R6, —C(O)—N(R6)(R7), —OC(O)—N(R6)(R7), —S—R6, —S(═O)—R6, —S(═O)2R6, —S(═O)2—N(R6)(R7), —S(═O)2—O—R6, —N(R6)(R7), —N(R6)—C(O)—R7, —N(R6)—C(O)—O—R7, —N(R6)—C(O)—N(R6)(R7), —N(R6)—S(═O)2—R6, —CN, and —O—R6,        wherein alkyl, cycloalkyl, heterocyclyl, phenyl, and phenoxy are optionally substituted by 1, 2, or 3 substituents selected from alkyl, cycloalkyl, alkoxy, hydroxyl, and halo;        wherein R6 and R7 are independently selected from the group consisting of hydrogen, C1-C15 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, all of which are optionally substituted with 1-3 substituents selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, —CN, lower alkoxy, —CF3, aryl, and heteroaryl; or        R6 and R7 when taken together with the nitrogen to which they are attached form a heterocycle;            R2 is hydrogen, halo, cyano, alkoxy, or alkyl optionally substituted by halo;            R3 is aryl, heteroaryl, or heterocyclyl, all of which are optionally substituted with one or more substituents selected from alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, oxo, —NO2, haloalkyl, haloalkoxy, —CN, —O—R6, —O—C(O)—R6, —O—C(O)—N(R6)(R7), —S—R6, —N(R6)(R7), —S(═O)—R6, —S(═O)2R6, —S(═O)2—N(R6)(R7), —S(═O)2—O—R6, —N(R6)—C(O)—R7, —N(R6)—C(O)—O—R7, —N(R6)—C(O)—N(R6)(R7), —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)(R7), and —N(R6)—S(═O)2—R7, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl is further optionally substituted with one or more substituents selected from halo, oxo, —NO2, alkyl, haloalkyl, haloalkoxy, —N(R6)(R7), —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)(R7), —CN, —O—R6, cycloalkyl, aryl, heteroaryl and heterocyclyl;with the proviso that the heteroaryl or heterocyclyl moiety includes at least one ring nitrogen atom;        X1, X2, X3, X4, X5, X6, X7 and X8 are independently C(R4) or N, in which each R4 is independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, —NO2, haloalkyl, haloalkoxy, —CN, —O—R6, —S—R6, —N(R6)(R7), —S(═O)—R6, —S(═O)2R6, —S(═O)2—N(R6)(R7), —S(═O)2—O—R6, —N(R6)—C(O)—R7, —N(R6)—C(O)—O—R7, —N(R6)—C(O)—N(R6)(R7), —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)(R7), or —N(R6)—S(═O)2—R7, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is further optionally substituted with one or more substituents selected from halo, oxo, —NO2, —CF3, —O—CF3, —N(R6)(R7), —C(O)—R6, —C(O)—O—R7, —C(O)—N(R6)(R7), —CN, —O—R6; or        X5 and X6 or X6 and X7 are joined to provide optionally substituted fused aryl or optionally substituted fused heteroaryl; andwith the proviso that at least one of X2, X3, and X4 is C(R4);            at least two of X5, X6, X7, and X8 are C(R4); and    at least one of X2, X3, X4, X5, X6, X7 and X8 is N.
The above disclosures notwithstanding, there is a need for compounds that are potent and exhibit improved pharmacokinetic and/or pharmacodynamic profiles for the treatment of diseases related to ASK1 activation.
Surprisingly, applicants have discovered a novel compound within the scope of U.S. patent publication US2011/0009410A exhibiting good potency, improved pharmacokinetic and/or pharmacodynamic profiles, on aggregate, compared to compounds disclosed therein.